Genetic Variant LOXL1:p.Arg87Ser (chr15-73927042-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005576.4(LOXL1):c.259C>A(p.Arg87Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000834 in 1,199,146 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R87G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 8.3e-7 ( 0 hom. )

Consequence

LOXL1
NM_005576.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.69

Publications

0 publications found

Variant links:

Genes affected

LOXL1 (HGNC:6665): (lysyl oxidase like 1) This gene encodes a member of the lysyl oxidase family of proteins. The prototypic member of the family is essential to the biogenesis of connective tissue, encoding an extracellular copper-dependent amine oxidase that catalyzes the first step in the formation of crosslinks in collagen and elastin. The encoded preproprotein is proteolytically processed to generate the mature enzyme. A highly conserved amino acid sequence at the C-terminus end appears to be sufficient for amine oxidase activity, suggesting that each family member may retain this function. The N-terminus is poorly conserved and may impart additional roles in developmental regulation, senescence, tumor suppression, cell growth control, and chemotaxis to each member of the family. Mutations in this gene are associated with exfoliation syndrome. [provided by RefSeq, Jan 2016]

LOXL1 links:

LOXL1-AS1 (HGNC:44169): (LOXL1 antisense RNA 1)

LOXL1-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005576.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LOXL1	NM_005576.4	MANE Select	c.259C>A	p.Arg87Ser	missense	Exon 1 of 7	NP_005567.2	Q08397
LOXL1-AS1	NR_040066.1		n.133+612G>T		intron	N/A
LOXL1-AS1	NR_040067.1		n.133+612G>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LOXL1	ENST00000261921.8	TSL:1 MANE Select	c.259C>A	p.Arg87Ser	missense	Exon 1 of 7	ENSP00000261921.7	Q08397
LOXL1	ENST00000856631.1		c.259C>A	p.Arg87Ser	missense	Exon 1 of 6	ENSP00000526690.1
LOXL1	ENST00000566011.5	TSL:5	n.259C>A		non_coding_transcript_exon	Exon 1 of 8	ENSP00000457827.1	H3BUV8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.34e-7

AC:

AN:

1199146

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

579824

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24218

American (AMR)

AF:

0.00

AC:

AN:

12832

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17688

East Asian (EAS)

AF:

0.00

AC:

AN:

26874

South Asian (SAS)

AF:

0.00

AC:

AN:

48108

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41796

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4014

European-Non Finnish (NFE)

AF:

0.00000103

AC:

AN:

975314

Other (OTH)

AF:

0.00

AC:

AN:

48302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.12

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.60

M_CAP

Pathogenic

0.32

MetaRNN

Uncertain

0.43

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

PhyloP100

1.7

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.8

REVEL

Benign

0.14

Sift

Uncertain

0.0040

Sift4G

Benign

0.079

Polyphen

0.99

Vest4

0.44

MutPred

0.34

Loss of helix (P = 0.0138)

MVP

0.57

ClinPred

0.93

GERP RS

3.2

Varity_R

0.21

gMVP

0.57

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over